Alkadienyl pyridyl and phenyl alkylene diamines, and method of preparing same



Patented .Tan. 20, i953 UNITED STATE s PATENT KOFIFICE -.ALKADIENYLPYRIDYL PHENYL AL- 'KYLENE DIAMINES, AND"'JMETHOD F 'PREPARING SAME William A..Lott, Maplewood, and Edward Pribyl, New Brunswick, N. J assignors- -to. Math-ieson Chemical Corporation, New York, .N..-..Y., ascorporation of Virginia (No Drawing. Application-September 28,1950, Serial No. 187,344

- (lower alkyl) R'- -NH(lower alkylene)-N (lower alkyl) in an organic solvent for the reactants in the presence'of'an alkaline condensing-agent, Rfhaving -the meaning :given hereinbefore.

"'[The terms lower salkylene', "-low.er,a1l y and alkadienyl :are employed .herein, in their broad sense, hence include branched BIS'EWBILZLS straight-chains] The preferred compounds of thisiinvention are those in-- which R. is 2-pyridyl, and/or ithe..:low.er alky'lenep.- .ishethylene, rand/or .=.-each.::ofthe lower alkyl groups is methyl.

The compounds of this invention are valuable histamine-antagonizing agents, being therapeutically effective in the treatment of nasal allergies, urticaria, ang-ioneurotic edema, serum sickness, and .t'reactions from penicillin, streptomycin, sulfonamiclesv and "other drugs, and being more potent and/orless toxicthan the prior compounds not embodying the alkadienylor'zhaloalkadienyl groups.

The, alkaline; condensing agent utilizable for the purposes of this invention comprise so-damide, lithium amide .(metallic),ealkali-metals (such as sodium and potassium), and (solid) alkali metal hydroxides (such as NaOI-I and KOl-I), inter alia.

The organic solvent for the reactants should, of course, be substantially-dry and inert. Solvents utilizable for the purposes of this invention comprise, in addition to the preferred aromatic hydrocarbons (such as toluene, benzene, and the xylenes): aliphatic hydrocarbons (such as hexane and heptane), and cycloaliphatic hydrocarbons (such as cyclohexane), and mixtures thereof, inter alia.

The bases obtained by the condensation may 7.01aims. (O1. 260+296) beconverted into addition ,-.salts..,wit h .,ac'ids. i,n

thev conventional manner, 1. e., .byareactingiflthe base: with the-desired acid in a suitable solvent. The xutilizable acids comprise: hydrochloric, hydrobromic, borio, nitric, lactic, tartaric/citric, succinic,,phosphoric, sulfuric, m aleit.v andgfii maricacids, inter alia. One or,..bo tli.of thesbasic oups may be s salified, by (u in -til ppropriate quantity of acid, yielding for -.example..the monoorpdi-hydrochloride.

The followin examples are illustrative Of the invention:

f2-.[ iedimethylamz'noethyl) .(heradz'enymflile amino] pyridine, and salts thereof (a) Preparation of"2%(5 dimethylaminoethyl) (heradienyLZA) -amin0l. pyridine.A solution, oi 6'7 g.. of "2'- eedimethylaminoethyl) -amino] pyridine EJ.A; 'C.S;"6'7,"394 (1945) 68,2001 (1946)1 in, 150. m1. of toluene is .addediw h st lf ll vasuspension of ll.2 g.vof sodamide in 159ml. of toluene. .After the initial reaction has subsided, the mixtureis refluxed for ,onehour, cooled, and 58 g. of 2,4-hexadienyljchloride'[l-lelv. Chim,;Acta. 15, 256 (1932)] ,in 200 ml. of. tolueneisadded dropwise. The mixtureis refluxed for two; hours, cooled and filtered; and the solvent is removed under reduced pressure. The residue is fractionated at reduced pressure, yielding about 32 g. of a base. fififi m thylaminoethyh (h xadienyl,2,4) aminol pyridine, 1boi1in g ;atabout*l3=1- 135 C./0.5 mm.

(11) Preparation of the v1 1/drochlorz'de of the basep one eq va ent of;2, alcoholic hydrogen chloride is added ,22, g. of the base; and .the solution isdiluted withether .and'flltered. 11eqrystanization .of .,-the precipitat I om -.me hy ethyl ket n gives, about. 1%,. 'aoiaw ite crysta line material, the monobydrochlori r fig-[Klidimethylaminoethyl) ,..(hexadienyl;2.,r1j) -.amin py din mel ing ati hout.l'3' ;l'38i C- i (b: alternative) Preparation of the 'dihydrochloride of the base-By adding two equivalents of the alcoholic hydrogen chloride to the base, the white crystalline dihydrochloride is obtained, melting at about ZOO-202 C.

(b: alternative) Preparation of the maleate of the base.A solution of 1.94 g. of maleic acid in 5 ml. isopropanol is added to 4.1 g. of the base in 5 ml. of isopropanol; and the solution is diluted with ether and filtered. The precipitate 2-[( 3- dimethylaminoethyl) (hexadienyl,2,4) amino] pyridine maleate recrystallized from isopropanol,

is a white crystalline product melting at about 131-132 C. (yield about 4.0 g.).

EXAMPLE 2 2-[03 dimethylaminoethyl) (3 chZoro hexar dz'enyl, 2,4) -amz'no] pyridine, and maleate thereof (a) Preparation of 2-[(p-dimethylaminoethyl) (3-chloro 2,4-hexadienyD-amz'no] pyridine-A solution of 67 g. of 2-[(B-dimethylaminoethyhamino] pyridine in 150 ml. of toluene is added with stirring to a suspension of 20.7 g. of sodamide in 200 ml. of toluene. After the initial reaction has subsided, the mixture is refluxed for one hour, cooled, and 80 g. of 1,3 -'dich1oro-2,4-hexadiene [J. A. C. S. 55, 2048 (1933)] in 200 ml. of toluene is added dropwise. The reaction mixture is refluxed for ten hours, cooled, and filtered; and the solvent is removed under reduced pressure, and the residue rapidly distilled at 0.3 mm. pressure. Refractionation of the distillate yields about 41.6 g. of the unreacted pyridine and about 38.2 g. of a pale yellow base, 2-[(,B-dimethylaminoethyl). (3-chloro-2,4-hexadienyl) amino] pyridine; the product boils at about 145-150 C. (0.3 mm. pressure) and has an n 1.5660.

(2)) Preparation of the maleate of the base.- A solution of 13.1 g. of maleic acid in 60 ml. of isopropyl alcohol is added to 32.68 g. of the base in 100ml. of-isopropyl alcohol, and the resulting crystals are recovered. After two crystallizations from 100 ml. portions of isopropyl alcohol, about 24.0 g. of the maleate is obtained as a colorless, needle-like, crystalline product, melting at about 134-135 C.

' EXAMPLE 3 2- [(gamma diethylaminopropyl) (hexadienyl, 2,4) -amz'no] pyridine, and salts thereof Using a molar equivalent of 2-[(gamma-diethylaminopropyD-amino] pyridine [J. A. C. S. 67, 394 (1945)] in place of the 2-[(,3-dimethylaminoethyl)-amino] pyridine in Example 1, 2- [(gamma-diethylaminopropyl) (hexadienyl,2,4) amino] pyridine, as Well as its hydrochlorides and maleate, are obtained.

EXAMPLE 4 l,(B-dimethylaminoethyl) (hexadienyl,2,4)-amino] benzene, and salts thereof 1 Using a molar equivalent of [(fi-dimethylaminoethyl) -amino] benzene [J. A. C. S. 68, 1999 (1946)] in toluene in place of the 2-[(p2-dimethylaminoethyl) -amino] pyridine in Example 1, [(fi-dimethylaminoethyl) (hexadienyl, 2, 4)- amino] benzene, as well' as its hydrochlorides and maleate, are obtained.

The invention may be variously otherwise embodied within the scope of the appended claims.

We claim: 1. A compound of the class consisting of: bases of the general formula (lower alkyl) R-N-(lower alkylene)-N (lower alkyl) wherein R is a member of the class consisting of hexadienyl,2,4 and 3-chloro-hexadienyl,2,4, and R is a member of the class consisting of phenyl and 2-pyridyl groups; and acid-addition salts thereof. 7

2. An acid-addition salt of a base of the general formula (lower alkyl) R-N-(lower a.lkylene)-N (lower alkyl) wherein R is a member of the class consisting of hexadienyl,2,4 and 3-chloro-hexadienyl,2,4, and R is a member of the class consisting of phenyl and 2-pyridyl groups.

3. An acid-addition salt of a base of the general formula (lower alkyl) (hexadienyl, 2,4)-N- (lower alkylene)-N (lower alkyl) 4. An acidaddition salt of a base of the general formula (lower alkyl) (3-chIoro-hexsdienyl, 2,4)N(lower alkylene)-N (lower alkyl) N 5. An acid-addition salt of 2-[(B-dimethy1- aminoethyl) (hexadienyl,2,4)-amino] pyridine.

' 6. An acid-addition salt of 2-[(,8-dimethylaminoethyl) (3 chloro-hexadienyl,2,4) -aminol pyridine.

7. The method which essentially comprises interacting a member of the group consisting of 2,4-hexadienyl chloride and 1,3-dich1oro-2,4- hexadiene with a compound of the general formula lower alkyl) R--HN(lower alkylene)- (lower alkyl) in an organic solvent for the reactants, in the presence of an alkaline condensing agent, R being a member of the class consisting of phenyl and 2-pyridyl groups.

WILLIAM A. LOTT. EDWARD PRIBYL.

N 0 references cited. 

1. A COMPOUND OF THE CLASS CONSISTING OF: BASES OF THE GENERAL FORMULA 